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Folic Acid Found Ineffective in Reducing Colorectal Adenomas


HANOVER, N.H. -- Folic acid supplements did not decrease the risk of new large-intestine adenomas, researchers here reported.

HANOVER, N.H., June 6 -- Folic acid supplements did not decrease the risk of new large-intestine tumors, researchers here reported.

Furthermore, at two follow-up intervals, patients taking folic acid tended to have higher rates of advanced and multiple adenomas than those in a placebo group reported Bernard F. Cole, Ph.D., of Dartmouth, and colleagues, in the June 6 issue of the Journal of the American Medical Association.

Biological and epidemiological evidence had suggested that folate supplementation might help prevent colorectal neoplasia, said Dr. Cole and the other members of the Polyp Prevention Study Group.

To evaluate the chemopreventive effect of folate in secondary prevention, the researchers conducted a double-blind, placebo-controlled, two-factor, randomized trial at nine clinical centers, from July 6, 1994 to Oct. 1, 2004.

Patients included 1,021 men and women with a recent history of colorectal adenomas and no previous invasive large-intestine carcinoma.

Of the patients, 516 were randomly assigned in a 1:1 ratio to receive 1 mg/d of folic acid while 505 were given a placebo. The participants were also separately randomized to receive aspirin (81 or 325 mg/d) or placebo. Follow-up consisted of two colonoscopic surveillance cycles (the first at three years, and the second, three or five years later).

During the first three years, 987 participants (96.7%) had a colonoscopy. Overall, there was no effect of folic acid supplementation on the development of adenomas, the researchers found, with risk ratios of 1.04 at three years and 1.13 at the second follow-up.

Among the folic acid patients, 44.1% (n=221), developed at least one colorectal adenoma; 42.4% of placebo patients (n=206) did (unadjusted risk ratio [RR], 1.04; 95% confidence interval 0.90-1.20; P=0.58).

At least one advanced lesion was found in 11.4% of folic acid patients (n=57) and 8.6% in those on placebo (n=42) (unadjusted RR, 1.32; CI, 0.90-1.92; P=0.15).

A total of 607 participants (59.5%) underwent a second follow-up. During that procedure, at least one colorectal adenoma was found in 41.9% of the folic acid group (n=127) and 37.2% of the placebo group (n=113) (unadjusted RR, 1.13; 95% CI, 0.93-1.37; P=0.23).

However, at the second follow-up, at least one advanced lesion was found in 11.6% of the folic acid group and 6.9% of the placebo patients. This amounted to a 67% increased risk of having at least one advanced lesion (unadjusted RR, 1.67; CI, 1.00-2.80; P=0.05), the researchers reported.

Folic acid was also associated with a higher risk (RR 2.32; P=0.007) of having three or more adenomas (30 individuals, 9.9%) compared with placebo patients (13 individuals, 4.3%).

There was also a higher rate of noncolorectal cancers, specifically prostate cancer, among those taking folic acid, the researchers reported. They had 24 cases of prostate cancer (7.3%) compared with nine (2.8%) in the placebo group (P=0.01). However, the researchers noted, this finding may have been spurious, given the number of adverse events evaluated.

Finally, the investigators wrote, there was no significant effect of sex, age, smoking, alcohol use, body mass index, baseline plasma folate, or aspirin allocation. Randomized aspirin did not significantly modify the effect of folic acid on advanced adenomas in the first follow-up interval (P=0.34).

These results may have been affected by fortification of the food supply with folate, which began in 1996, shortly after the start of enrollment in this study, the researchers said.

Not only did folic acid supplementation over six years fail as secondary prevention for new colorectal adenomas, the investigators said, but supplementation may also increase the risk of some tumors.

However, the evidence for an increased risk of adenomas is "equivocal" and suggests the need for further research, they wrote.

In view of the fortification of the U.S. food supply with folate, and some suggestions that folate could conceivably increase the risk of neoplasia even outside the colorectum, this line of investigation should have a high priority, Dr. Cole's team concluded.

In an accompanying editorial, Cornelia M. Ulrich, Ph.D., and John D. Potter, M.D., Ph.D., of the Fred Hutchinson Cancer Center in Seattle, asked, "How should the unexpected results of this study be interpreted?"

The most likely explanation for the increased risk of advanced and multiple adenomas in the intervention group, they posited, is that undetected early precursor lesions were present in the mucosa of these patients, who are at increased adenoma risk, and that folic acid promoted these lesions.

This hypothesis, they said, is consistent with experimental studies showing increased colorectal neoplasia when folic acid is administered after lesions are present.

By the nature of the study's design, the results do not provide information on primary prevention, or on the effect of folic acid supplementation among individuals with unresected colorectal polyps, the editorialists wrote.

Because the timing of folate administration during carcinogenesis matters, the results of this study highlight the need for research on the role of folate and carcinogenesis, they said.

First, they suggested, a better understanding is needed about the dosage, duration, and timing effects of folic acid on the growth of early neoplastic lesions and slow-growing tumors, including, for example, a subset of prostate cancers.

Second, they said, the need for information on the effects of folic acid among individuals with unresected polyps is critical. Research on patients with cancer should also be a high priority.

The results of the clinical trial by Dr. Cole and colleagues illustrate once again the principle that chemoprevention with single agents is problematic, Drs. Ulrich and Potter said. "It is time to be as thoughtful about the need for multiagent chemoprevention, not forgetting that diet is one version of this, as we are about the use of multiagent chemotherapy."

The editorial writers, Drs. Ulrich and Potter, had no financial disclosures to report. Their work was supported by grants from the National Institutes of Health.

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